Sorafenib is an active pharmaceutical ingredient approved for the treatment of the primary kidney cancer, for the treatment of advanced primary liver cancer and radioactive iodine resistant advanced thyroid carcinoma.
Sorafenib, also named BAY 43-9006 and abbreviated SRFB, is marketed in form of tosylate salt, in particular, in form of monotosylate salt, i.e. a salt made by one molecule of paratoluensulfonic acid per one molecule of Sorafenib.
Sorafenib tosylate is a non-chiral molecule having the following formula (I):
and has chemical name 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide 4-methylbenzenesulfonate (1:1).
The synthesis of Sorafenib was disclosed in detail in the patent publication EP1140840, in Organic Process Research & Development (OPRD), 2002, 6, 777-781, in Drug of the Future (2002), 27(12), 1141-1147 and in OPRD, 2013, 17(2), 221.
The synthesis disclosed in patent EP1140840, named Route A, particularly in examples A2, B1 and C1a, appears an attractive route of synthesis for the preparation of Sorafenib.
The later publication WO2006034796 discloses the industrial synthesis of Sorafenib on multi Kgs scale wherein specific conditions to perform the coupling step are disclosed in detail. Method 5a discloses the preparation of Sorafenib tosylate form I, i.e. Sorafenib tosylate having crystalline or polymorphic form named form I.
The active pharmaceutical substance Sorafenib tosylate shows polymorphism and many crystal forms are currently known.
In the patent publication EP1797038 the applicant states that the polymorph included in the marketed pharmaceutical composition is the thermodynamically stable polymorph, i.e. the polymorph having melting point 223-231° C., also named form I or polymorph I.
In the same document EP1797038 are disclosed and well characterized other solid forms of Sorafenib, in particular:                Sorafenib tosylate form II, having m.p. 194° C., being a metastable form,        Sorafenib tosylate form III, having m.p. 187-190° C.,        Sorafenib tosylate methanol solvate, that loses 4.8% by weight in TGA,        Sorafenib tosylate ethanol solvate, that loses 6.7% by weight in TGA.        
According to the teaching of EP1797038, par. 6, the crystalline form or polymorph named form II was already part of the state of the art since it was first disclosed in example 1 of WO00/42012.
In particular EP1797038 discloses the preparation of Sorafenib tosylate form I treating with an inert solvent Sorafenib tosylate form II from 50° C. up to reflux temperature. The working example 2 provides some procedures for the conversion of form II to form I.
Sorafenib tosylate form II was prepared in example 1 of EP1797038 starting from Sorafenib base.
The publication EP1797038 also discloses a method for the preparation of Sorafenib tosylate form III treating Sorafenib tosylate form II with an inert solvent, e.g. with methanol. Filtration is performed after from 1 day to 1 week, and the product is dried and heat-treated at from 145° C. to 160° C. for from 15 minutes to 1 hour. Working example 3 provides an embodiment of the said conversion of form II to form III by slurring form II in methanol for one week at room temperature.
The publication EP1797038 discloses a method for the preparation of Sorafenib tosylate ethanol solvate treating Sorafenib tosylate form II with ethanol. Filtration is performed after 1 week, and the product is dried. Working example 5 provides an embodiment of such conversion of form II to Sorafenib tosylate ethanol solvate by slurring form II in ethanol for one week at room temperature. After filtration, the product was dried at room temperature.
Sorafenib tosylate ethanol solvate has the following formula (I-EtOH):
and has chemical name 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide 4-methylbenzenesulfonate, compound with ethanol (1:1:1) or 2-Pyridinecarbaxamide, 4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-, 4-methylbenzenesulfonate, compound with ethanol (1:1:1).
The biggest drawback of the above described procedure for the preparation of Sorafenib tosylate form III and Sorafenib tosylate ethanol solvate is that the starting material for said procedure, i.e. Sorafenib tosylate form II is a metastable form, as declared in EP1797038 itself. Indeed, according to our experimentations, once Sorafenib toyslate form I is obtained for the first time, it is not more possible to produce Sorafenib tosylate form II. Therefore, the methods disclosed in EP1797038 for the preparation of Sorafenib tosylate form III and Sorafenib tosylate ethanol solvate, are not suitable for routine preparations of said compounds and are not scalable for larger productions, indeed it would be extremely difficult to obtain and to maintain the form II and therefore to control its conversion to form III.
The publication WO2009/092070 discloses in the working examples 2-4 the preparation of Sorafenib tosylate methanol solvate by treating a solution of Sorafenib base in methanol or in NMP with a methanolic solution of paratoluenesulfonic acid monohydrate.
The publication WO2009/092070 also discloses in the working example 5 the preparation of Sorafenib tosylate methanol solvate by treating a solution of Sorafenib tosylate form I in a mixture of DMSO and methanol with paratoluenesulfonic acid monohydrate.
Example 6 of WO2009/092070 is particularly important since it discloses for the first time the preparation of Sorafenib tosylate form III by treating Sorafenib tosylate methanol solvate at 80° C. under vacuum for 16 hours.
Example 7 of WO2009/092070 discloses the preparation of Sorafenib tosylate ethanol solvate by stirring a suspension of Sorafenib toyslate form III in ethanol for 48 hours.
Example 8 and 11 and examples 9, 10, 12 of WO2009/092070 disclose for the first time the preparation of Sorafenib hemi-tosylate respectively from Sorafenib tosylate form III in water or from Sorafenib base in isopropanol, n-propanol or acetone. When Sorafenib hemi-tosylate is prepared from Sorafenib base, paratoluensulfonic acid monohydrate was added.
The publication WO2014/118807 in examples 1 and 2 discloses a method for the preparation of Sorafenib tosylate ethanol solvate by addition of paratoluensulfonic acid monohydrate to a suspension of Sorafenib base in ethanol and further stirring for respectively 7 or 3 days.
Then Sorafenib tosylate form III was obtained by drying under vacuum at 80-85° C. for 20-22 hours Sorafenib tosylate ethanol solvate.
Both the experiments 1 and 2 of WO2014/118807 have been reworked using absolute ethanol and it was observed that in both the experiments 1 and 2, after 10 minutes by the end of the addition of paratoluensolfonic acid, Sorafenib tosylate form I was obtained substantially in quantitative manner. Then, stirring form I in absolute ethanol for at least 6 days (not before since for example after only 5 days there are residual amounts of form I) Sorafenib tosylate ethanol solvate is obtained.
It is thus clear that the procedure disclosed in WO2014/118807 starts from Sorafenib base, then is produced Sorafenib tosylate form I which is slowly converted in ethanol into Sorafenib tosylate ethanol solvate. Therefore said procedure thus passes through the transient specie being Sorafenib tosylate form I which is formed in situ and slowly converts to Ethanol solvate form.
Sorafenib tosylate ethanol solvate obtained according to the experiments 1 or 2 of WO2014/118807, i.e. prepared by a process wherein Sorafenib tosylate form I is appeared, although as transient form, does not provide polymorphic pure Sorafenib tosylate form III.
Indeed, performing the step II of experiments 1 and 2 of WO2014/118807, using Sorafenib tosylate ethanol solvate prepared in step I, the Sorafenib tosylate form III thus prepared is contaminated by form I.
Moreover, the problem due to the presence of the form I as impurity of the form III is magnified by increasing the scale, indeed just a sample of about 5 grams of Sorafenib tosylate ethanol solvate (as in example 1 WO2014/118807) can be dried/converted in form III at 80-85° C. in 20-22 hours, since the preparation of form III, for example at Klab scale, requires much higher temperature to complete the conversion of Sorafenib tosylate ethanol solvate into Sorafenib tosylate form III in reasonable time. To the other side, high temperature promotes the conversion of Sorafenib tosylate form III into Sorafenib tosylate form I (the form thermodynamically stable) especially when Sorafenib tosylate form III contains little amounts, traces or also microseedings of Sorafenib tosylate form I.
Thus, with the aim of preparing Sorafenib tosylate form III with a scalable process that can be also applied for industrial productions, it is mandatorily essential to set up a process for preparing Sorafenib tosylate form III which avoid absolutely and completely the appearance of Sorafenib tosylate form I.
Finally, Sorafenib tosylate form III as prepared have to comply with the stability stress studies which includes the study of the prolonged stability at high temperature. To this aim it is essential that Sorafenib tosylate form III does not contain any microseed or microcrystal of form I otherwise that seed triggers and catalyzes the conversion of form III to form I.
The “stability stress” requirements can be satisfied only if in the process for the preparation of sorafenib tosylate form III and related precursor intermediate Sorafenib tosylate ethanol solvate, there is not appearance of Sorafenib tosylate form I.
In other words, avoiding the appearance of Sorafenib tosylate form I during a process for the preparation of Sorafenib form III and intermediates thereof, e.g. during the preparation of Sorafenib tosylate ethanol solvate, it can be produced Sorafenib tosylate form III with increased stability towards the conversion to the termodinamically stable form being Sorafenib tosylate form I.